Earlier results have indicated that there is a relative mean deficiency of erythrocyte NaK-ATPase activity in bipolar affective disorder, and that this can be normalized by therapy with lithium salts. The proposed research here will investigate these findings further. Longitudinal studies in subjects with bipolar affective disorder and unipolar depressive disorder will determine whether individual fluctuations in parameters of erythrocyte-NaK-ATPase activity show correlations with affective state (manic, depressed, or normothymic), mode of therapy, and duration of illness. Parameters of NaK-pump activity and of clinical response will be measured before and during lithium therapy on groups of subjects with bipolar affective, unipolar-depressive, and schizoaffective disorders, schizophrenia, and other psychiatric disorders to determine whether an increase in NaK-pump activity during lithium therapy is specific for bipolar affective disorder, and whether it has any potential as a predictor of therapeutic or prophylactic response. Kinetic characteristics and other properties of the erythrocyte membrane NaK-ATPase will be compared in bipolar affective subjects and in non-polar subjects to try to find conditions which might give a greater resolution of the difference in bipolar affective disorder. The possibility of developing a diagnostic test for bipolar affective disorder based on the difference will be explored. An attempt will be made to determine whether a genetic variant of the NaK-ATPase is involved in bipolar affective disorder. Inbred strains of mice will be screened to try to find a genetic strain in which chronic administration of lithium salts may lead to a substantial increase in brain NaK-ATPase activity. If successful, this will be used as an animal model system in which to study the mechanism of action of lithium on brain NaK-ATPase.